Understanding the interactions of environmental factors, such as diet, with fine molecular mechanisms involved in carcinogenesis will lead to new prevention strategies that will drastically reduce cancer incidence in this country. Russell D. Klein, Ph.D. is a junior investigator committed to an academic career in cancer prevention. He has graduate training in nutrition, animal science, and cancer biology and has been involved in cancer related research for over ten years. The mentored support afforded by this award will provide an excellent opportunity for Dr. Klein to develop an independent externally funded research program. The career development and research aims in this proposal will be carried out at Science Park Research Division, a component of the internationally recognized comprehensive cancer center, the University of Texas M.D. Anderson Cancer Center in Houston, TX. The completion of these aims will involve interactions between several different departments within UT M.D. Anderson Cancer Center including Carcinogenesis, Veterinary Medicine, Epidemiology, Clinical Investigation, and Clinical Cancer Prevention. The research aims in this proposal involve the use of a transgenic mouse line (K14.COX2) that overexpresses cyclooxygenase 2 (COX-2) in prostate cells. These mice develop neoplastic lesions in the prostate and represent a novel model for studying the mechanisms by which of COX-2 products effect prostate carcinogenesis. This project will test the hypothesis that changes in the amount and type of dietary fatty acids fed to K14.COX2 mice will influence the incidence and severity of neoplastic lesions in the prostate through changes in prostaglandin synthesis. The aims are designed to provide information for developing rational prevention strategies based on altering prostaglandin synthesis by diet or drugs. The first three specific aims are focused on determining the ability of dietary fatty acids and a COX-2 inhibitor to alter: 1) eicosanoid levels in the prostates of K14.COX2 transgenic mice; 2) cellular proliferation, apoptosis, and genes involved in invasion and angiogenesis in the prostates of K14.COX2 mice; and 3) the incidence and severity of hyperplasia, dysplasia, and neoplasia in K14.COX2 mice. The fourth specific aim involves characterizing the prostaglandin receptors involved in prostaglandin regulation of cell proliferation, apoptosis, VEGF and matrix metalloprotease gene expression in prostate cancer cell lines. This research is anticipated to lead to further pre-clinical trials and ultimately to rationally designed clinical prevention studies aimed at determining the ability of dietary fatty acid changes to influence prostate cancer progression. The proposed research and career development aims will provide the framework for Dr. Klein to develop an independent academic research career based on the use of novel models of cancer for mechanistic cancer prevention studies, and will facilitate the necessary collaborations for involvement in clinical cancer prevention research.